The purpose of this project is to apply current methods for detection and analysis of polymorphic genetic markers to linkage analysis of cystic fibrosis in especially informative families. The project involves a collaboration between the laboratories directed by L.O. Cavalli-Sforza and Mary-Claire King in order to locate and sample sufficient families and survey an adequate number of polymorphic DNA and protein markers. The specific aims of the project are: (1) to select families especially informative for linkage studies of cystic fibrosis; (2) to screen all available polymorphic DNA and protein markers, with the aim of locating the cystic fibrosis gene (cf) within a reasonably small distance of a marker locus; and (3) if this is successful, to look for new polymorphic markers closer to cf. By applying present techniques for detecting polymorphisms at the DNA level to genetic analysis of cystic fibrosis, it is now possible, in principle, to precisely locate cf on the human genome. However, the very large number of markers and families required to obtain adequate information for linkage analysis of a recessive disease gene whose protein product is unknown would seem to make such an effort impractical. In order to make linkage analysis of cystic fibrosis feasible, this project will exploit two tricks of sampling design and laboratory technique. First, the study sample will include only families with at least two living, affected children and both parents available. Such families include about seven times as much information as families with one affected and one unaffected child and considerably more information than even very large sibships with only one affected child. Second, screening for DNA markers potentially linked to cf will employ multiple probes and mixtures so that up to ten polymorphisms can be analyzed simultaneously. These features will reduce the total number of tests sufficiently that it is reasonable to propose locating cf with considerable precision in a relatively short time. Finding a genetic marker reasonably close to cf could enable prenatal diagnosis of cystic fibrosis in families at high risk and detection of carriers in such families.